Primary brain tumors consist of a diverse group of neoplasms, derived from various different cell lineages. Pursuant to a World Health Organization categorization (Louis et al., 2007), tumors of the central nervous system are classified as astrocytic, oligodendroglial, or mixed (oligoastrocytic). These tumors are further classified by subtypes and are graded, based on histology, from 1 to IV, with grade IV being the most aggressive. Glioblastoma multiforme (GBM), the most aggressive form of primary malignant brain tumor, accounts for approximately 45% to 50% of all primary brain tumors (Wrensch et al., 2002; Behin et al., 2003) and represents the second largest cause of cancer death in adults under 35 years of age (Allard et al., 2009).
Despite numerous therapeutic efforts, including cytoreductive surgery, radiation therapy and chemotherapy, the prognosis for glioma patients remains very poor (Stewart, 2002; Stupp et al., 2005). A majority eventually develop recurrent and progressive disease, after which the median survival is approximately 6 months (Wong et al., 1999; Lamborn et al., 2008). Median survival for GBM patients is about 12-14 months (Stupp et al., 2005).
In addition, brain metastasis from primary tumors such as breast, lung, and skin (melanoma) is a significant and growing public health problem. An estimated 250,000 patients in the United States were diagnosed with brain metastases in 2009 (Fox et al., 2011), which is more than 10-fold greater than the incidence of primary brain tumors (Jemal et al., 2009). The prognosis for patients with brain metastases is very poor, and most patients live only 4-6 months after diagnosis. Current treatment regimens provide marginal survival benefits (Eichler and Loeffler, 2007).
Complete surgical resection of gliomas is almost impossible, due to their diffusely infiltrative nature and proximity to vital brain structures. Systemic therapy also is limited, by virtue of the so-called blood brain barrier (BBB). See, generally, Cecchelli et al. (2007).
This barrier resides within the brain's capillary endothelium, and it has been an object of study for over 100 years. Indeed, the fact that most drug candidates for brain tumors never make it to the clinic (Pardridge, 2007) is attributable largely to their inability to cross the BBB and reach levels having a therapeutic effect (Groothuis, 2000).
Despite extensive efforts over several decades, the curative rates in the treatment of brain cancers remain abysmal. Brain cancer treatment thus represents one of the biggest challenges in oncology. Furthermore, the prevailing consensus is that the BBB is the major limiting factor in drug delivery into brain tumors.
Accordingly, considerable effort is directed globally to discovering and developing new drugs that are small enough to cross the BBB and improve the survival outcome for GBM patients. In addition, techniques are under development to transport drugs past the BBB and into the brain tumor microenvironment.
Among the approaches that have been studied, in an attempt to circumvent the BBB limitation, are the following.                Hyperosmotic BBB disruption (Kroll and Neuwelt, 1998).        Chemical barrier modification (Black et al., 1997).        Attempts to link therapeutic agents to compounds that have transporters across the BBB (Bickel et al., 2001; Zhang and Pardridge, 2007).        Direct administration of drugs into and around brain tumors (Hassenbusch et al., 2002; Hai et al., 2002; Reardon et al., 2002; Weber et al., 2002). This approach entails placement of drug-loaded wafers around a tumor resection bed, infusion of agents into or around a tumor resection cavity, or direct infusion of drugs into the tumor mass.        Convection-Enhanced Delivery or “CED” (Bobo et al., 1994; Morrison et al., 1994; Hadjipanayis et al., 2008; Hadjipanayis et al., 2010). In CED a small hydrostatic pressure differential is imposed by a syringe pump to distribute infusate directly to regions of the central nervous system (CNS). CED is a minimally invasive surgical procedure that provides fluid convection in the brain by a pressure gradient, which bypasses the BBB. Therapeutic agents can be delivered into the brain with a minimum of the toxicity, therefore, as well as to normal tissue and to organs commonly accessed by systemic delivery.        